HUT74170A - Bicyclic tetrahydro pyrazolopyridines - Google Patents

Description

The present invention relates to a series of bicyclic tetrahydropyrazolopyridines which are selective inhibitors of type IV phosphodiesterase (PDE) and inhibit the production of tumor necrosis factor (TNF), such as asthma, arthritis, bronchitis, chronic respiratory disease, psoriasis, allergic , dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases related to TNF production.

The invention also relates to the use of such compounds in the treatment of mammals, including man, and to pharmaceutical compositions containing them.

Since the discovery that cyclic AMP is a second intracellular messenger [E.W. Sutherland and T. W. Rali, Pharmacol. Port. 12, 265 (1960)], inhibition of phosphodiesterases has been the target of modulation and has accordingly been directed to the therapeutic control of many diseases. Recently, some of the PDEs have a number of actives: 82940-4185-KY / KmO ♦ · · · β · · · · · ····· ··· ·

- recognized 2 ports [J.A. Beavo and D.H. Reifsnyder, TiPS, 11, 150 (1990)], and their selective inhibition has led to better drug therapy [C.D. Nicholson, R.A. Challiss and M. Shahid, TiPS, 1-2, 19 (1991)]. In particular, it has been recognized that inhibition of type IV PDE may lead to inhibition of inflammatory mediator release [M.W. Verghese et al., J. Mol. Cell. Cardiol., 12 (Suppl. II), p. 61 (1989)] and resulted in airway smooth muscle relaxation [T.J. Torphy, Directions for New Anti-Asthma Drugs, editors: S.R. O'Donnell and C.G. A. Persson, 37, Birkhauser (1988). Thus, type IV PDE inhibitors exhibit weak activity against other types of PDE, but they inhibit the release of inflammatory mediators and relax airway smooth muscle without producing cardiovascular effects or anti-platelet effects.

TNF has been recognized to be involved in many infectious and autoimmune diseases [W. Friers, FEBS Letters, 285, 199 (1991)]. In addition, TNF has been shown to mediate an inflammatory response in sepsis and septic shock (C.E. Spooner et al., 1992, Clinical Immunology and Immunopathology, 62, 11).

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R ¹ is hydrogen, C 1-7 alkyl, C 2-3 alkenyl, C 3-5 cycloalkyl, or methylene (C 3-5). cycloalkyl) wherein each alkyl or alkenyl group may be optionally substituted with up to two C 1 -C 2 alkyl or trifluoromethyl groups or up to three halogens;

- 3 X is oxygen or two hydrogen,

R ² and R ³ independently of one another are hydrogen, C 1 -C 14 alkyl, C 1 -C 14 alkoxy, C 2 -C 7 alkenyl, C 4 -C 7 heterocyclic groups containing oxygen or sulfur, SO ₂ or NR ⁵ wherein R ⁵ is hydrogen, (C 1 -C 4) alkyl, or (II) wherein a is an integer from 1 to 5;

b and c are 0 or 1,

R ⁴ is hydrogen, hydroxy, C 1-5 alkyl,

C 2 -C 6 alkenyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkoxy, halogen, trifluoromethyl, CO ₂ R ⁶ , CONR ⁶ R ⁷ , NR ⁶ R ⁷ , NO ₂ or SO ₂ NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are each independently hydrogen or C 1-4 alkyl; where

Z is oxygen or sulfur, SO ₂ or NR ⁸ where R ⁸ is hydrogen or C 1-4 alkyl,

Y is (C 1 -C 5) alkylene or (C 2 -C 6) alkenyl substituted with up to two (C 1 -C 7) alkyl or (C 3 -C 7) cycloalkyl groups, or (a) wherein p is 1 to 3,

W is oxo or hydroxy;

R ⁹ is C 1 -C 3 alkyl, wherein each alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group is optionally 1 to 14, preferably

May be substituted with 1-5 groups, and wherein these groups may be C 1 -C 2 alkyl, trifluoromethyl or halogen, provided that R ¹ is ethyl and R ⁴ is methylphenyl R ^{3 is} not hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl, provided that R ² is 4-ηηβίιΊ-ίβηιβ-θ8οροοί and R ³ is 4-. fluorophenyl, then R ¹ cannot be phenyl, methyl or n-propyl, and with the proviso that when R ¹ is ethyl, R ^{2 is} phenyl, then R ³ cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, with the proviso that when R ^{1 is} ethyl and R ² is 4-methoxyphenyl, then R ³ cannot be 4-fluorophenyl.

More particularly, the present invention relates to a compound of formula (I) wherein R ¹ is C 1 -C 3 alkyl and R ² and R ³ are each independently C 3 -C 7 cycloalkyl, C 4 -C 7 heterocyclyl which is SO ₂ or (III). wherein R ⁴ is hydrogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or halogen.

The invention further relates to a compound of formula I wherein R ^{1 is} ethyl or isopropyl, R ^{2 is} phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxy. phenyl or 3-trifluoromethylphenyl; and R ^{3 is} cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.

• · · · ··················································································································· · · · · · · · · · · ···

The invention further relates to a pharmaceutical composition for inhibiting phosphodiesterase type IV, i.e. PDE, and inhibiting the production of tumor necrosis factor, i.e. TNF, which comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to inhibit phosphodiesterase type IV and TNF production.

The present invention further provides for the treatment of inflammatory conditions in a mammal by administering an anti-inflammatory amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The invention further relates to a pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic respiratory disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases related to TNF production. Or a pharmaceutically acceptable salt thereof, together with a pharmaceutically effective amount of a pharmaceutically acceptable carrier.

The invention further encompasses the prevention of asthma, arthritis, bronchitis, chronic respiratory disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other TNF production related diseases.

Or treating the patient by administering to the patient an effective amount of a compound of formula (I) and a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention include:

3-ethyl-1- (4-methoxyphenyl) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-ethyl-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1 H-

- pyrazolo [3,4-c] pyridine;

3-ethyl-1- (3,4-dichlorophenyl) -6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c] ] pyridine;

3-ethyl-1-cyclopentyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine;

3-Ethyl-1- (4-fluorophenyl) -6- (2-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine ;

3-Ethyl-1-cyclopentyl-6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyrid tendon;

3-ethyl-1-cyclopentyl-6- (3-trifluoromethyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-ethyl-1-cyclohexyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-Isopropyl-1-cyclopentyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine;

3-ethyl 1-1-cyclobutyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-ethyl-1-cyclopentyl-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-ethyl-1-cyclopentyl-6- (2-methyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine;

3-ethyl-1- (3-sulfolyl) -6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3, 4-c] pyridine;

3-Ethyl-1- (3-sulfonylanyl) -6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c] ] pyridine;

3-ethyl-1-cyclobutyl-6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-Ethyl-1- (3-sulfolanyl) -6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine ;

3-ethyl-1-cyclobutyl-6- (3-trifluoromethyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine;

3-ethyl-1-cyclobutyl-6- (2-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine.

In the application, the term halogen refers to chlorine, fluorine and bromine.

The alkyl, alkoxy and alkynyl groups may be straight chain or, when they contain 3 or more carbon atoms, may be straight, branched or cyclic, or may be a combination of cyclic, branched or straight chain groups.

The inflammatory disease that can be treated according to the present invention includes, but is not limited to, asthma, chronic obstructive pulmonary disease, bronchitis, and arthritis.

R ^1, R ² and R ³ are as defined above. The following reaction schemes illustrate, but are not limited to, the preparation of the compounds of the present invention.

In Reaction 1, Scheme 1, the 2-pyrrolidinone compound of formula (IV) can be converted to the corresponding N- (aryl) -2-pyrrolidone of formula (V) wherein aryl is a group of formula (II) such that The compound of formula (IV) is reacted with an aryl halide in the presence of a pure copper powder and potassium carbonate. Suitable aryl halides include 1-iodo or 1-bromo-4-methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4-methylbenzene, 2-methylbenzene, -trifluoromethylbenzene, 2-trifluoromethylbenzene, 3,4-dimethoxybenzene or 3-cyclopentoxy-4-methoxybenzene. The reaction temperature is generally 110 to 170 ° C, preferably 150 ° C, and the reaction time is 14 to 22 hours, preferably 18 hours, and the reaction is carried out under inert conditions.

In Scheme 1, Reaction 2, halide R ^{1 is} added to a suspension of magnesium in anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed and then cooled to -15 and 15 ° C, preferably 0 ° C. The N-aryl-2-pyrrolidone compound (V) is then added and the mixture is warmed to room temperature while stirring for 1.5-2.5 hours, preferably 2 hours. Bromomethane, bromoethane or bromopropane may be used as the alkyl halide. The preferred anhydrous aprotic solvent may be anhydrous ether. After completion of the reaction, the desired intermediate can be isolated in a known manner, for example by first washing the combined organic materials with water and brine, then drying over sodium sulfate, filtering, evaporating under reduced pressure to obtain an easily recoverable precipitate as a white solid.

The above precipitate is converted to the corresponding 1,2,5,6-tetrahydropyridine of formula (VI) by dispersing the precipitate in a mixture of apolar aprotic solvent and base.

«·« · · · V · · · · · · · · · · · · · · · · · · · · · · · · · ·

Under vigorous stirring, ethyl oxalyl chloride is added and the reaction mixture is heated under reflux for 1.5 to 4.5 hours, preferably for 3 hours. The preferred apolar aprotic solvent is benzene, and the preferred base is sodium hydroxide. The solvents were removed and the resulting residue was treated with a solution of sodium alkoxide in ethanol. The mixture is heated under reflux for 1 to 3 hours, preferably 1.5 hours, then concentrated under reduced pressure and acidified to pH 3 with hydrochloric acid.

In Scheme 1, Reaction 3, a compound of formula (VI) is converted to a 3-methoxy-1,2,5,6-tetrahydropyridine of formula (VII) by reacting the compound of formula (VI) with 3-methyl-1- heated with p-tolyltriazine in an aprotic solvent. The aprotic solvent is preferably 1,2-dichloroethane. The reaction time is from 30 minutes to 120 minutes, preferably 45 minutes.

Reaction Scheme 2, Reaction 1, has the formula (VIII)

1,2,5,6-tetrahydropyridine, where R ^{5 is} hydrogen or methyl, is converted to the corresponding 4,5,67-tetrahydro-7-ΟΧΟ-1H-pyrazolo [3,4-c] pyridine of formula IX reacting a compound of Formula VIII with hydrazine R ³ HNNH ₂ . Both derivatives of the compound (VIII), i.e. the 3-hydroxy and 3-methoxy derivatives, can also be used as starting materials under one of the three reaction conditions.

Under one reaction condition, the 1,2,5,6-tetrahydropyridine compound of Formula VIII can be converted to the compound of Formula IX by reacting a compound of Formula VIII with hydrazine hydrochloride and sodium alkoxide in anhydrous polar protic solvent. The preferred sodium alkoxide is sodium methoxide, and

V * · ·· * ♦ · V · · · · · · · · · · · ···

The preferred anhydrous polar protic solvent is anhydrous ethanol. The reaction mixture is heated at reflux for 9-15 hours, preferably 12 hours.

In the second reaction condition, the 1,2,5,6-tetrahydropyridine of formula (VIII) may be converted to the compound of formula (IX) by reacting a compound of formula (VIII) with hydrazinobenzoic acid in anhydrous polar protic solvent, preferably ethanol. The reaction mixture is heated to reflux for 16-24 hours, preferably for 20 hours. The resulting compound of formula IX is further reacted to give the corresponding 1- (4-benzamide) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine by reacting the compound of formula (IX) with sodium methoxide in a polar protic solvent, preferably methanol, for 15 to 45 minutes, preferably 30 minutes. The polar protic solvent is removed under reduced pressure, the solid residue is suspended in an apolar aprotic solvent, preferably benzene, and the apolar solvent is removed under reduced pressure. The resulting dry solid was suspended in cold ether and treated with oxalyl chloride and N, N-dimethylformamide. Stir for 30 to 90 minutes, preferably 60 minutes. The solvent was then removed and the crude residue dissolved in anhydrous tetrahydrofuran. The resulting solution is added dropwise to stirred ammonium hydroxide at -10 to + 10 ° C, preferably at 0 ° C.

The third reaction condition is represented by the formula (VIII)

1,2,5,6-Tetrahydropyridine is converted to compound (IX) by reacting compound (VIII) with hydrazine hydrochloride in a polar protic solvent, preferably methanol. THE

the reaction mixture is heated to 70-110 ° C, preferably 90 ° C, under a gentle stream of nitrogen until all solvent is removed. The pure mixture is then heated to 120-180 ° C, preferably to 150 ° C for 30-90 minutes, preferably 60 minutes.

The resulting compound of formula IX can be converted to the corresponding 6-R ² -4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-c] pyridine, wherein R ^{2 is} other than A group of formula (II) in which a solution of a compound of formula (IX) in a polar aprotic solvent, preferably acetonitrile, is reacted with a solution of ammonium cerium (IV) nitrate in water at -15 to + 15, preferably at 0 ° C. - 50 minutes, preferably 35 minutes. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The combined organic materials were then washed with saturated sodium bicarbonate followed by sodium sulfite. The compound thus obtained is treated with sodium hydride in a polar aprotic solvent, preferably tetrahydrofuran, heated to reflux and stirred for 30 to 60 minutes, preferably 45 minutes. The reaction mixture is cooled to 20-30 ° C, preferably 25 ° C, and an alkyl halide of the formula R ^{2 is} added, where R ² is other than the group (II) above. The reaction mixture is heated and stirred under reflux for 12 to 20 hours, preferably 16 hours.

In Scheme 2, Reaction 2, a 2-oxo-4,5,6,7-1H-pyrazolo [3,4-c] pyridine of formula (IX) is converted to a compound of formula (X): The reaction mixture is stirred for 12 to 20 hours, preferably 16 hours, and then water and a base, preferably sodium hydroxide, are added, followed by addition of water and a base, preferably sodium hydroxide. • ···· · · · · · · · · · · · · · · ·

The reaction mixture is stirred and filtered for 1.5-2.5 hours, preferably 2 hours. The filtrate was evaporated to give a white solid.

The following in vitro assay demonstrates the ability of compounds or pharmaceutically acceptable salts thereof to inhibit phosphodiesterase type IV (PDE <) and, accordingly, are effective in treating inflammatory diseases.

Biological Experiment (Human Lung PDEiv)

30-40 g of human lung tissue was placed in 50 mL of pH 7.4 Tris / phenylmethylsulfonyl fluoride (PMSF) / sucrose buffer and homogenized with Tekmar Tissumizer® (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249). at full speed for 30 seconds. The homogenate is centrifuged at 48,000 g for 4 minutes at 4 ° C. The supernatant was filtered twice through a 0.22 µm filter and applied to a Mono-Q FPLC column (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) previously equilibrated with Tris / PMSF pH 7.4. A flow rate of 1 ml / min was used and the same sample was applied to the column and subsequently washed and eluted at a flow rate of 2 ml / min. The sample was eluted with a stepwise gradient of sodium chloride in Tris / PMSF pH 7.4. Fractions of 8 ml were isolated. Fractions were assayed for specific PDE _iV activity as determined by [ ³ H] cAMP hydrolysis, and the ability of a known PDEiv inhibitor (e.g., rolipram) to inhibit hydrolysis was determined. The appropriate fractions were combined, 2 ml ethylene glycol / 5

ml of enzyme preparation containing ethylene glycol and stored at -20 ° C until use.

The compounds were dissolved in DMSO, diluted with water (400 pmol, 4% DMSO) at a concentration of 10 ml and 1:25. Further serial dilutions were made in 4% DMSO to achieve the desired concentrations. The final DMSO concentration in the test tube is 1%. Add the following quantities in duplicate into a 12 x 75 mm glass tube (all concentrations are the final concentration in the test tube):

i) 25 μΙ compound or DMSO (1%, control and blank) ii) 25 μΙ Tris buffer pH 7.5 iii) [ ³ H] cAMP (1 pml) iv) 25 μΙ PDEiv (for blank, enzyme hot) incubate in water for 5 minutes in advance)

The test tubes are shaken and placed in a 37 ° C water bath for 20 minutes, at which time the reaction is stopped by placing the test tubes in a hot water bath for 4 minutes. In an ice bath, 0.5 mL of 0.1 M 4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid (HEPES) / 0.1 M sodium chloride (pH 8.5) was added to each tube and added to each tube. the contents of the tubes were loaded onto Affi-Gel 601 column (Biorad Laboratories, POBox 1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinity gel, 1 mL bed volume) previously equilibrated with wash buffer [ ³ H] cAMP Wash with ml of wash buffer, elute the [ ³ H] 5'AMP with 4 ml of 0.25 M acetic acid. 1 ml of eluate in a suitable vial after vortexing.

to 3 ml of scintillation fluid, again subjected to vortexing and counting [ ³ H].

% inhibition = 1 - ^cpm ^ ^tlag (test compound - cpm mean (blank) ⁹ cpm mean (control) - cpm mean (blank)

The ICso is determined so that the concentration of the compound which inhibits 50% of the [HjcAMP hydrolysis' ^[3 H] 5'AMP-protecting.

TNF

The effect of the compounds of the invention and their pharmaceutically acceptable salts on inhibiting TNF production and subsequently demonstrating the treatment of diseases related to TNF production is demonstrated in the following in vitro experiment.

Peripheral blood from human volunteers (100 ml) was collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells were isolated with Ficoll / Hypaque and washed three times in incomplete HBSS. Cells were resuspended in a final concentration of 1 x 10 ⁶ cells / pre-warmed RPMI (RPMI contains 5% FCS, glutamine, pen / step and nystatin). Monocytes 1 x 10 ml ^6/1 plated in 24 well plates. The cells were incubated at 37 ° C with 5% carbon dioxide and allowed to adhere to the plates for 2 hours and then the non-sticky cells were removed by gentle washing. 10 μΙ of test compound was then added to the cells at 3-4 concentrations and incubated for 1 hour. Add 10 μΙ LPS to the appropriate wells. The plates were incubated overnight at 37 ° C for 18 hours. At the end of the incubation period, TNF was sandwiched «·

- analyzed by 15 ELISAs (R&D Quantikine Kit). The IC ₅₀ determination for each compound is performed by linear regression analysis.

Pharmaceutically acceptable acid addition salts of the compound of the invention may be formed from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, para-toluenesulfonic acid, acetic acid, gluconic acid, maleic acid, and succinic acid. The pharmaceutically acceptable cationic salts of the compounds of formula (I) of the present invention wherein R ⁴ is CO ₂ R ⁶ and R ^{6 are} hydrogen, such as sodium, potassium, calcium, magnesium, ammonium, Ν, Ν'-dibenzylethylenediamine, N-methylglucamine (Meglumine), ethanolamine and diethanolamine.

For the treatment of therapeutic and prophylactic inflammatory diseases in human administration, the compounds of formula (I) and their pharmaceutically acceptable salts are hereinafter referred to as oral dosages of generally 0.1 to 100 mg per day in an average patient of 70 kg. Thus, in a typical adult patient, the capsules or tablets contain from 0.1 to 50 mg of the active ingredient in admixture with a pharmaceutically acceptable carrier or diluent. For intravenous administration, the dose will usually be 0.1 to 10 mg / single dose as needed. For intranasal or inhalation administration, the dose will generally be 0.1 to 1% w / v solution. In practice, the physician will determine the exact dosage that will be most advantageous to the individual patient and this dosage may vary with the age, weight and response of the patient. The above dosages are exemplary of an average case, but in some cases are higher

Lower dose ranges can also be used and are within the scope of the invention.

For human administration, there are several conventional routes of administration for TNF inhibition, such as oral, parenteral or topical administration. In general, the active ingredient is administered orally or parenterally at a daily dose of 0.1 to 25 mg / kg body weight, preferably 0.3 to 5 mg / kg body weight per day. In some cases, it may be necessary to vary the dose depending on the condition of the patient being treated. The person in charge will always determine the appropriate dose.

For human use, the active ingredient of the invention may be administered alone, but will generally be administered in admixture with a pharmaceutically acceptable diluent or carrier, depending upon the intended mode of administration and standard medical practice. For example, they may be administered orally in the form of tablets, which may contain excipients such as starch or lactose, or in the form of an oval capsule, either alone or in admixture with the excipient, or in the form of an elixir or a suspension containing flavoring or coloring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, a sterile aqueous solution containing other substances, for example, enough salt or glucose, to render the solution isotonic, is most preferred.

Accordingly, the present invention also provides pharmaceutical compositions comprising pharmaceutically acceptable salts of the compounds of formula I in admixture with a pharmaceutically acceptable carrier or diluent.

- 17 • · · · · · · · · · · · · · · · · · · · · ···

Further details of the invention are illustrated by the following examples.

Example 1

3-Ethyl-1- (4-methoxyphenyl) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-

-1 H -pyrazolo [3,4-c] pyridine g, 4.1 mmol 3-hydroxy-2-oxo-1-phenyl-4-propionyl 1-1,2,5,6-tetrahydropyridine, 0, A mixture of 8 g (4.6 mmol) of 4-methoxyphenylhydrazine hydrochloride and 0.11 g (2 mmol) of sodium methoxide in 35 ml of anhydrous ethanol was heated under reflux. After 12 hours, the solvent was removed by rotary evaporation under reduced pressure and the crude residue was chromatographed on a 4 x 20 cm silica column. Elution with a 1: 1 mixture of ether and hexane afforded 345 mg of the title compound as a red oil which crystallized upon standing at room temperature. The desired 1- (4-methoxyphenyl) regioisomer is less polar than the 2- (4-methoxyphenyl) by-product.

Melting point: 43-45 ° C.

IR (chloroform) lactam C = O, 1665 ^cm-first

¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.32 (t, J = 7.6 Hz, 3H); 2.74 (q, J = 7.6 Hz, 2H); 2.96 (t, J = 6.6 Hz, 2H); 3.79 (s, 3H); 4.10 (t, J =

6.6 Hz, 2H); 6.89 (d, J = 9.0 Hz, 2H); 7.22-7.39 (m, 5H); 7.45 (d, J = 9.0 Hz, 2H);

Elemental analysis for C21H21N3O2:

Calculated: C, 72.60; H, 6.09; N, 12.09;

Found; C, 72.48; H, 6.08; N, 11.66.

MS m / z (M +) 347.

2-15. example

Reaction of the appropriate hydrazine hydrochloride with 4-alkanoyl-3-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine gives the following compounds analogously to Example 1:

Mass spectrum or analysis (found) % Ni 15.51 14,16 o o ▼ - T HRMS (M *) 315.1741 MS m / z [M +] 386 11.43 CM CM co f "1 ♦ N E ω S HRMS (M +) 309.1823 % H 6.77 7.96 6.07 5.37 sP (J 70.61 72.50 70.05 68.75 Mass spectrum or analysis (calculated) £ Z 16.46 14,13 11.13 (M *) 315.1747 [M * J 386.26 11.50 co CM CO + S (M +) 309.1841 % H rr ^ <O 7.79 6.14 5.52 She 70.56 72.70 70.01 69.03 Oh o Q. he 80-83 120-121 42-45 92-94 (oil) 129-130 * GOOD Five 1 σ> CO 73-75 methyl tert-butyl 4-methoxy- phenyl tert-butyl 3,4-dichloro- phenyl 4-methoxy- phenyl 4-fluorophenyl cyclopentyl N or. phenyl phenyl 4-methoxy- phenyl 4-fluorophenyl phenyl 4-fluorophenyl phenyl phenyl .alpha. Φ ω Φ ethyl ethyl ethyl methyl ethyl example Number CXI co Shoot <O 00 ώ

E 3 zis (found) 11.72 11.75 9.86 *] 286 1 co Ν ' CD Φ + + She SHE m 5 Q. 1 R to r- SHOOT tendon tendon N c σ> co N 0) to ω Ν ' ω Φ χ- CN CN V Ν ' C E Ό 0) ra αι co co S Yeah co 'CO CD rue 8.0 CO o ω > I co T CO co CD CD CD co CD CD CD SHE T v- SHE E x- 3 u φ * w 77 89 -X N 'Τ co CO CD She 35 Φ n rö c Φ * φ * 'Τ. CN X 'T. CD TFI ο 333 388 m tendon N tendon 0) φ to ε CD CD CD 28 E 0> > to Ν co τ 7 co co m ♦ :SHE to 2 » co co She 1- > co CD CD Λ SHE C0 CN 00 She CD NT co χ- x- x- She 1 • —X 1 1 CD CL h- to She co to SHE CD V She Ν ' co x- 50 She ntil E E 1 1 φ φ φ u. X Q. M M "SHE ο -L 1- L_ -X + * φ Ε E eni luo luo • 0 1 c Φ »+ - M M 'St. φ Φ oc RA M Shoot 4 co co M E 1 X 1 X 1 X 1 X She She She She + * » __ Φ Φ Φ Φ N Ε Έ E I E I E I E c Φ 0 < Φ Μ- Φ u- Ν ' · Ή 1 N ΜΙ N CO 1 + - * L Φ Φ Φ [Οί Ε Φ E E Φ Φ DA E > to "Φ N ό v ~ CN co 4 tendon CL </) Χ " x- x-

Recrystallization solvents ^are isopropyl ether. ^b 5% Ethyl Acetate in Petroleum Ether «* · · · ·······················································

Example 16

3-Ethyl-1- (4-phenylcarboxylic acid) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-1 H -plrazolo [3,4-c] pyridine g, 4.08 A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydropyridine, 0.68 g, 4.49 mmol of 4-hydrazinobenzoic acid and 30 ml of anhydrous ethanol was refluxed. heat under refrigeration. After 20 hours, the mixture was concentrated on a rotary evaporator under reduced pressure and the solid residue was suspended in a mixture of 500 mL of ethyl acetate and 200 mL of pH 4 buffer. The organic phase is separated (most of the 2- (4-phenylcarboxylic acid) is a by-product), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from methanol gave 0.64 g of the title compound as an orange solid, m.p. 261-263 ° C.

¹ H-NMR (300 MHz, DMSO-d ₆ ) d 1.23 (t, J = 7.6 Hz, 3H); 2.68 (s, J = 7.6 Hz, 2H), 2.94 (t, J = 6.5 Hz, 2H); 4.05 (t, J = 6.5 Hz, 2H); 7.20-7.41 (m, 5H); 7.65 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 13.05 (s, 1H);

MS m / z (M ⁺ ) 362.

Example 17

- (4-Benzamide) -3-ethyl-6- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

To a stirred solution of sodium methoxide (6.6 mg) in methanol was added 3-ethyl-6- (4-methoxyphenyl) -1- (4-phenylcarboxylic acid) -7-oxo-96 (96 mg, 0.25 mmol), 5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine. After 30 minutes, the methanol was removed under reduced pressure and the solid residue in benzene was removed under reduced pressure. ·

- 22 suspended. The benzene was removed under reduced pressure. The resulting dry solid was suspended in cold ether in an ice bath and treated with 31 μΙ, 0.35 mmol oxalyl chloride and 1 drop of anhydrous Ν, Ν-dimethylformamide. After stirring for 1 hour, the volatiles were removed under reduced pressure and the crude residue was dissolved in anhydrous tetrahydrofuran. The resulting solution was added dropwise at 0 ° C to rapidly stirred ammonium hydroxide. After heating over 2 hours to room temperature, the reaction mixture is concentrated under reduced pressure until a yellow solid begins to precipitate. At this time, the mixture was diluted with water to about 100 mL, filtered and the precipitate washed with water to give 81 mg of the title compound, which decomposes at 243-245 ° C.

¹ H-NMR (DMSO-d ₆ ) 1.24 (t, J = 7.6 Hz, 3H); 2.68 (q, J = 7.6 Hz,

2 H); 2.93 (t, J = 6.5 Hz, 2H); 3.75 (s, 3H); 3.99 (t, J = 6.5 Hz,

2 H); 6.94 (d, J = 9.1 Hz, 2H); 7.27 (d, J = 9.0 Hz, 2H); 7.43 (s,

1H); 7.59 (d, J = 8.5 Hz, 2H); 7.90 (d, J = 8.6 Hz, 2H); 8.04 (s,

1H).

Elemental analysis for C22H22N4O3:

Calculated: C, 67.68; H, 5.68; N, 14.35;

Found: C, 67.19; H, 5.31; N, 13.55.

HRMS calcd for C22H22N4O3 [M ⁺ ] 391.1770; found: 391.1771.

The starting 3-ethyl-6- (4-methoxyphenyl) -1- (4-phenylcarboxylic acid) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine was prepared from the appropriate reagents as in Example 16.

Example 18

1- (3,4-dichlorophenyl) -3-ethyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] ] pyridine

0.49 g, 1.7 mmol 3-methoxy-1- (3-methoxyphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine, 0.40 g, A stirred mixture of 87 mmol of 3,4-dichlorophenylhydrazine hydrochloride and 46 mg of 0.85 mmol of sodium methoxide in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column. A mixture of ethyl acetate and hexane (1: 4) was used as eluent. The resulting white solid was recrystallized from ether to give 0.46 g of white needles.

Melting point: 97-99 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ) 1.31 (t, J = 7.5 Hz, 3H);

2.73 (q, J = 7.6 Hz, 2H); 2.96 (t, J = 6.6 Hz, 2H); 3.79 (s, 3H); 4.09 (t, J = 6.6 Hz, 2H); 6.78-6.91 (m, 3H); 7.29-7.49 (m, 3H);

7.73 (d, J = 1.8 Hz, 1H);

MS m / z [M +] 416.

19-42. example

Suitable hydrazine hydrochloride and 4-alkanoyl-3-methoxy-2

The reaction of oxo-1,2,5,6-tetrahydropyridine according to Example 18 gives the following compounds:

• ·

Mass spectrum or analysis (found) i % N i 9.65 _ HRMS [M ⁺ ] 340.2046 11.69 12.70 HRMS [M *] 400.0966 MS m / z [M ⁺ ] 369 9.71 % H 1 4.02 1 7.68 7.10 -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- ---------------------------------------------- 1 4.46 c% 56.13 70.44 69.48 59.41 i Mass spectrum or analysis (calculated) % N 10.45 [M *] 340.2025 12.38 12.91 _________________________________________________________________i [M * J 400.0983 I [M *] 369.46 9.41 % H 4.26 CM xr CM r— ro 4.74 % C 59.71 70.77 70.13 59.20 SHE She CL he is 143-144 ' 64-65 96-98 121-122 oil 107-108 1 90-1 91 ^b ro QI 3,4-dichloro- phenyl cyclopentyl cyclopentyl cyclopentyl 3,4-dichloro- phenyl cyclopentyl 3,4-dichloro- phenyl * Qi 4-methoxy- phenyl 3-methoxy phenyl 4-methoxy- phenyl 4-methoxy- phenyl phenyl I 3,4-dimethoxy- phenyl 3,4-dimethoxy- phenyl T methyl ethyl φ methyl isopropyl φ φ 1 ίβ _C Ί3 C Φ n 0. tfí 19th She CM CM 22nd 23rd 24th 25th

• ·

Ε Φ * (Ό Φ ^ 9.53 11.73 9.97 bσ> b- ' οο 11.57 ΣΙ 4.Ν U <λ V φ * Ν 3- οο ο ο 04 φ C0 00 χ- ' ιο Μ 1 CL <0 (Q G 'φ b- ιη ιθ ' Ιθ ' I Ο) <0 Ν Φ σ> 00 ΙΟ ΙΟ ρ ιη Ε = Ο Ο) φ CM cn ο ιη χ- C \ l ω 0'6 Η > οο b- οο <0 οο σ> ο (0 οο οο ο ιο b- r- V Ε σ> V σ> 00 V 2 U V) φ * Ν C4 ο 04 'Τ lake C0 φ Q, Φ C φ * φ * σ> 1 ^ · σ> ν ιη b- (Λ ο Γ- 'φ ιθ ' οο 10 Ο) φ 04 Φ Ε ο <0 ο Ο ίΤ 00 Ε = ο Ο) φ «Φ Ν <0 '' Τ X C0 χ- τ- sf 04 ^_ + 0'6 Η > <Ω b- οο <Ο 00 ο ο ' Ό Φ Ο b ~ οο b ~ ο Ο Ί · ο 04 ^ τ τ ~ χ- χ- ΟΟ σ> Τ- 1 1 1 ΙΟ I C0 I 1 Q. ιο 04 ΟΟ σ> ^β 'φ Ο 04 V οο οο ο Τ'- χ- 10 οο X 1 1 1 c L.  - 4- U · - · Φ Μ- Ό Έ ο -ο ♦ "* C φ φ U. 1 U I Ε Q. Ο α 1 C Ό I 'c steal luo ST φ - «τ φ X φ Μ- I χ οο ' Μ- Ι Ο οο Η- 1 οο ' ο 4 X X 00 ο οό ο * Μ- C C X X X X φ X φ X ο ο ο ο ο. ο CL ο * - * Μ- » Q * - » Q . φ · - φ ♦ - φ φ  - φ Φ C C C c C C Ε C ε C Ε C ΓΜ φ φ φ φ - φ φ (Τ ν 1 Μ- Ι οό Μ— ί ν ο ΜΙ 0 Μ- Ι οο ΜΙ ο. Q. ο Ο U. L- ο. ο. Ο. οί οζι pro ΐζο ethyl ethyl «4» Φ DA Ε - • φ . * φ Ν οο rí οο σ> ό Q. ΙΛ 04 04 04 04 00 CO

··· ········································································ (

typ) 12.01 <Ό Γ 12.63 11:52 10.97 10.41 12.59 12.09 Ε (bowl 3 NEW u ω CO * + Ν ω Ο) ΙΟ (Ο οο (XI CXI οο V χ- 0 ¢ ΙΟ Ν ' ο ΙΟ ΙΟ CXI Q. <0 <Ό C ν ~ Ν ' ΙΟ ιο χτ Ν ' ιο 00 She) to Ν Ν Φ 00 Ε χ7 (Ο ΙΟ ο Ο (Ο Ε Ε σ> ra <0 ΙΟ ο σ> <ο ΧΓ- 00 ο ω χ7 CXI 0θ (XJ χ7 CXI ω Η > Ν- Ν ' Γ'- (Ο (Ο Ν ' Ν- C0 CD CXI ΟΟ CXI ΟΟ 00 C0 σ> ο χ- Χ7 σ> ο Ε CXI (χί (XI ν- ο CXI CXI χ- X ^- χ- τ- X "- X 3 U </> * » Ν CXI σ> Ν- Ν ' ΙΟ σ> Ν ' ο Q. 75 C χ7 χ7 Ν ' Ν ' ΟΟ CXI Ν ' Ν ' Φ (Λ ο Ν ' ιη Ν ' ΙΟ ιη χτ Γ'- ΙΟ C0 σ> <0 (Ο ΟΧΙ φ Ε Ν ' ΟΟ Ν- CD (Ο 00 Ν ' σ> 00 Ε : Ο Ο) CQ 'Φ Ν <0 0.7 ♦ CXJ χ7 2.1 3.6 2.5 4.2 CXI 1- > Ν ' Ν- Ν ' ω (Ο Ν ' Ν ' Λ Ο Ο χ7 ο CM χ- ο CXI ο χ7 χ7 οο Χ " Χ " V " Χ7 χ- ΧΓ ~ the 1 1 1 cn 1 I 1 α. σ> ΟΟ «Γ 7? αΓ σ> ΧΓ- ο ^β χ- ο ΟΟ 09 χ7 οο ο χ ^- X ο ο ο χ- σ> X X Έ C Έ Έ φ * - » φ φ φ C C Η- C Μ- C Μ- C φ L- φ U. φ L_ φ ι_ φ ο. Ο ο. ο Q. ο ο. ο CL ο ZJ ο = 7 Ο Ζ3 _ο_ JJ | Ο Μ- U JUI Μ- -X U .Χί οί ο χ7 ο • "φ Ο χ7 ο χ7 Ο nil C C C - C 1 | φ φ 1 C 1 C φ φ φ X ο X ο Μ- Ι ΜΙ fluoro l-fe fluoro l-fe * ♦ - 1 »♦ - 1 ΜΙ φ ' " φ φ φ Μ- Μ- φ φ φ Ν Ε 1 C φ Ε C φ Ε Ε 1-4— » φ Ε 1- φ Ε Ε Ε Ε 02 CXI 1 CXI 1 CO 00 ΟΟ 1 00 1 χ7 CXI CXI + ·· » 02 φ φ φ Φ φ φ Φ φ φ DA 1 Ε - <0 Ν CXI 00 xf ΙΟ (Ο Ν ' 00 σ> ό α. <0 00 00 ΟΟ 00 ΟΟ ΟΟ 00 (Ο Χ7

• · · ·

E 3 u zis (found) Φ Ξ3 She r "- Q. <Q M · C9 (Λ c φ SHE) (0 NI Φ E ^: O >. E E D) (0 ω co H > E 3 k-w (Λ X. N 3.38 r ^ - Φ Q. <0 C to T C9 O) Φ E φ <ü o> <B E Wow NI W 40 W 31 H > (/) She She She • io Melting point 1 00 'T oil phenyl alanyl M She L_ She □ □ N M </) QT 4 ώ E 1 c φ fluoro Φ ΜΙ ΜΙ H φ N * - * methyl E the: CXI co 4 » QI Φ φ (Q TJ E > <B . 4 » N T CXI 0th (Λ xr V

c 'OJ c Φ Q-

• · · ·

Example 43

-Cyclohexyl-3-ethyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

0.80 g, 2.8 mmol 3-methoxy-1- (3-methoxyphenyl) -2-oxo-4-propionyl-1,2,5,6-pyridine and 0.54 g, 3.6 mmol A solution of cyclohexyl hydrazine hydrochloride in 15 ml of methanol was heated at 90 ° C under a gentle stream of nitrogen until all solvents had been removed. The pure mixture was then heated to 150 ° C under a stream of nitrogen for 1 hour and then cooled to room temperature. The mixture was dissolved in ether, washed with 1N hydrochloric acid and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel, eluting with ethyl acetate / hexane (1: 1), afforded 0.47 g of the title compound as a yellow oil.

1 H-NMR (250 MHz, CDCl ₃ ) 1.20-1.52 (m, 6H, including 1.23 at J, 7.6 Hz, 3H); 1.64-1.74 (m, 1H); 1.80-2.06 (m, 6H);

2.67 (q, J = 7.6 Hz, 2H); 2.87 (t, J = 6.7 Hz, 2H); 3.82 (s, 3H);

3.97 (t, J = 6.7 Hz, 2H); 5.13 (tt, J = 4.3 and 11.3 Hz, 1H), 6.79-6.93 (m, 3H); 7.31 (t, J = 8.1 Hz, 1H);

HRMS calcd for C 21 H 27 N 3 O ² : [M ⁺ ] 353.2103; found: 353.2094.

44-57. example

Reaction of the appropriate hydrazine hydrochloride with 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine according to Example 43 gives the following compounds:

• ·

Mass spectrum or analysis (found) % N M m co ♦ <Z> 11.73 12.93 13.95 MS [M + J] 326 12.02 9.82 % H <0 m r- ' 7.22 7.08 5.91 6.03 i % C 71.10 70,10 73.34 72.35 58.46 Mass spectrum or analysis (calculated) % N 'T m co + * 11.89 12.91 14,23 [M * J 326 12.10 10.79 % H o b ~ Γ 7.12 7.17 6.09 5.95 % C 71.36 70.13 73.19 72.60 58.59 O a Q. SHE 102-103 ' XI o O v 1 σ> σ> xa 'T r- 1 CO Γ 60-62 ° oil xi Γ yrs 1 <D years oil Dhi cyclopentyl cyclopentyl cyclobutyl methylene -cyclopropyl methylene -cyclopropyl phenyl 3 szulfolanil B.C 4-methoxy- -fen i I 3-methoxy phenyl 3-methoxy phenyl phenyl 3-methoxy phenyl 4-methoxy- phenyl 3-methoxy phenyl r · the isopropyl isopropyl * - * Φ ethyl ethyl ethyl ethyl iPéldaIszám 44th 45th 46th 47th 48th 49th 50th

• · · · ·"·· ·the

E 3 k- X Φ Q. «0 nalysis (found) -------------------------------------------------- -------------------------------------------------- -------------------------------------------------- ---------------------------------------------- 1 60 01 · 13.03 428 11.19 CO o : 310 Iz 388, 389, 4.51 7.56 5.54 6.48 CD <u N N E Φ E = O > »DJ ra 3.40 3.22 E ω 3.01 7.35 E ω ω o CD 1- > CD r- CD r. S CO 04 00 CD CD V tendon m r- She co V X CO E T * " * " V 3 · » k_ (0 b- b- ** N ID CD 04 m CD 38 Φ * - * CO V m CL (0 ra c She V h ' CD Φ tendon CD CB CD Φ CD (Q E She E Φ E: O >, DJ <Q E 40 N <0 3.61 3.75 horse's more 2.80 7:28 IW 3 such as xylene h- > φ E CD E D • U tendon CD 04 She 04 m SHE χ- ▼ - X 04 • 1 1 1 CD Q. 24 ΈΓ FIVE 7? 55 00 10 She V She She She X CD ₌ c 1 c - (0 - - Five Φ u— 3 She M destinations E 3 c -L £ 1 _Q cu (0 M SHE N SHE T3 SHE D L_ Φ c c 4 » E 1 CO QI SHE co She 04 Ό C4 Έ ₌ c 1 φ 1 c 1 c Φ | X o * ♦ - 1 fluoro Φ * ♦ - 1 fluoro Φ Μ- Ι ΜΙ : oxy Φ ~~~ Φ M 4- ^ Φ φ * 77 N (T 3-m c Φ M— 3-m 1 ------------------------------------------------- ------ 3-tr Φ E 1 3-tr i Φ E 1 phenylene 2-m - 3-m C Φ u- 1 * - » QI Φ Φ Φ Φ Φ Φ Φ DA E * · · * φ N χ- 04 C0 V tendon CD bi 0th <0 tendon tendon tendon tendon m tendon tendon

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

petroleum ether; 'Ethyl acetate; ^f ethyl acetate / hexane.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 31 Example 58

3-Ethyl-6- (4-fluorophenyl) -1- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

3-Ethyl-6- (4-fluorophenyl) -1- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-0.3 g, 0.82 mmol To a stirred solution of pyrazolo [3,4-c] pyridine in 50 mL of ether was added 33 g, 0.86 mmol of lithium aluminum hydride. After stirring for 16 hours, 0.5 ml of water and 1 ml of 3N sodium hydroxide are added. After stirring for 2 hours, the white precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. Chromatography on silica gel. A 1: 3 mixture of ethyl acetate and hexane was used as eluent to give 0.12 g of the title compound as a pale yellow paste.

¹ H-NMR (250 MHz, CDCl ₃ ) 1.28 (t, J = 7.6 Hz, 3H); 2.66 (q, J = 7.6 Hz, 2H); 2.71 (t, J = 5.7 Hz, 2H); 3.49 (t, J = 5.7 Hz, 2H); 3.84 (s, 3H); 4.23 (s, 2H); 6.84-6.99 (m, 6H); 7.36 (d, J = 9.0 Hz, 2H);

MS m / z [M ⁺ ] 352.

59-63. example

Reaction of the appropriate 7-oxo-2,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine with lithium aluminum hydride afforded, by analogy to Example 58, the following compounds:

• ·

I

CM CO

Mass spectrum [M ⁺ ] (found) ! 409 371.373 296 312 340 mw 409.57 372.30 295.43 311.43 339.48 Oh o Q. he oil ! oil oil oil oil w QI cyclopentyl 3,4-dichloro- phenyl cyclopentyl cyclobutyl cyclohexyl So 4-methoxy-3-cyclopentoxy phenyl phenyl phenyl 3-methoxy phenyl 3-methoxy phenyl £ 0 ethyl ethyl φ ethyl ethyl example Number 59th 09 T <Ö 62nd 63rd

Example 64

-Cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

1-Cyclopentyl-3-ethyl-6- (4-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [2.58 g, 7.60 mmol] A stirred solution of c] pyridine in 90 mL of acetonitrile was treated at 0 ° C with a solution of 12.5 g, 22.8 mmol of cerium ammonium nitrate in 110 mL of water. After stirring for 35 minutes, the mixture was diluted with water (550 mL) and extracted with ethyl acetate (4 x 100). The combined organics were washed with 250 mL of 50% saturated sodium bicarbonate followed by 10% sodium sulfite until the aqueous wash was pale yellow. The organic phase is then further washed with saturated sodium bicarbonate and brine and then treated with activated carbon. After stirring for 30 minutes, the mixture was dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The brown residue was recrystallized from ether to give 0.814 g of a tan solid, m.p. 143-145 ° C.

MS (M / Z) 234;

¹ H NMR (250 MHz, CDCl 3) 1.21 (t, J = 7.6 Hz, 3H); 1.62-2.13 (m, 8H); 2.62 (q, J = 7.6 Hz, 2H); 2.73 (t, J = 6.8 Hz, 2H); 3.51 (dt, J = 2.7 and 6.8 Hz, 2H); 5.61 (pentet, J = 7.7 Hz, 1H).

Example 65

-Cyclopentyl-3-ethyl-6-cyclopropylmethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine

A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine (0.21 g, 0.92 mmol) in tetrahydrofuran (5 mL) • ···· · · · · ···· · ··· ···

- treat 34 with 40 mg, 1.01 mmol of 60% sodium hydride in mineral oil. After stirring under reflux for 45 minutes, the mixture was cooled to 25 ° C and 0.31 g (2.29 mmol) of bromomethylcyclopropane was added. The mixture was stirred at reflux for 16 hours, cooled to 25 ° C and evaporated under reduced pressure. Chromatography on silica gel, eluting with ethyl acetate: hexane (1: 1), afforded 0.19 g of the title compound as a colorless oil.

MS m / z [M +] 288;

¹ H-NMR (300 MHz, CDCl ₃ ) 0.26-0.31 (m, 2H); 0.50-0.56 (m, 2H); 0.85-1.06 (m, 1H); 1.20 (t, J = 7.6 Hz, 3H); 1.62-2.08 (m, 8H); 2.61 (q, J = 7.6 Hz, 2H); 2.74 (t, J = 6.8 Hz, 2H); 3.39 (d, J = 6.9 Hz, 2H); 3.63 (t, J = 6.8 Hz, 2H); 5.67 (pentet, J = 7.8 Hz, 1H).

Reference Example 1

4-Isobutyl-3-methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine

A stirred solution of freshly distilled diisopropylamine (0.16 mL, 2.21 mmol) in dry tetrahydrofuran (4 mL) was cooled to 0 ° C and treated with n-butyllithium (0.85 mL, 2.11 mmol). After 15 minutes, the mixture was cooled to -78 ° C and 4-propionyl-3-methoxy-1-phenyl-2-oxo-1,2,5,6- (0.52 g, 2.0 mmol) was added dropwise via cannula. tetrahydropyridine as a pre-cooled solution in tetrahydrofuran (4 mL). After 20 minutes, methyl iodide (0.20 mL, 3.0 mmol) was added to the light orange red solution and the mixture was allowed to warm to room temperature for 2.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on a silica gel column, eluting with ethyl acetate / hexane (1: 4), afforded 0.12 g of the title compound as a yellow oil, yielding 0.1 g more of the starting material.

¹ H-NMR (250 MHz, CDCl ₃ ) 1.15 (d, 6H); 2.72 (t, 2H);

3.47 (heptet, 1H); 3.82 (t, 2H); 3.97 (s, 3H); 7.21-7.45 (m, 5H); MS m / z [M ⁺ ] 274.

2-3. reference example

The corresponding 3-methoxy-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine is reacted with lithium diisopropylamine and methyl iodide in analogy to Reference Example 1 to give the following compounds of formula VII:

Reference example number R ² Mp (° C) molecular Weight Mass Spectrum [M ⁺ ] Second 4-methoxy- phenyl oil 303.36 304 Third 3-methoxy phenyl oil 303.36 304

Reference Example 4

3-Methoxy-1- (4-methyl-phenyl) -2-oxo-4-propionyl 1-1,2,5,6-tetrahydropyridine

5.9 g (23 mmol) of 3-hydroxy-1- (4-methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine and 5.1 g (34 mmol) of 3-methyl- A solution of 1-p-tolyltriazine in 1,2-dichloroethane was heated at reflux for 45 minutes. Allow the mixture to cool to room temperature - 36 -

is poured into water and acidified with 6N hydrochloric acid. The aqueous phase was extracted three times with methylene chloride and the combined organics were washed with 1N hydrochloric acid, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting quantitative brown oil was pure by chromatography and ¹ H NMR and could be used without further purification.

¹ H NMR Spectrum (300 MHz, CDCl ₃ ) 1.12 (t, J = 7.2 Hz, 3H);

2.34 (s, 3H); 2.71 (t, J = 6.7 Hz, 2H); 2.93 (q, J = 7.2 Hz, 2H);

3.77 (t, J = 7.8 Hz, 2H); 3.94 (s, 3H); 7.20 (s, 4H);

MS [M ⁺ ] 273.

5-14. reference example

By reaction of the appropriate 3-hydroxy-1-aryl-2-oxo-4-alkanoyl-1,2,5,6-tetrahydropyridine with 3-methyl-1-p-tolyltriazine according to the procedure of Reference Example 4 below, Compounds of formula VI are obtained.

Reference example number R ¹ R ² Mp (° C) molecular Weight Mass Spectrum [M ⁺ ] 5th ethyl phenyl oil 259.31 260 6th methyl 4-methoxy- phenyl oil 275.30 275 7th ethyl 4-methoxy- phenyl 81-82 289.33 289 8th n- propyl 4-methoxy- phenyl oil 303.36 303 9th ethyl 3-methoxy phenyl 59-60 289.33 289, 290

Reference example number R ¹ R ² Op ( ^e C) molecular Weight Mass spectrum 1 * 0 10th ethyl 2-methoxy phenyl oil 289.33 289 11th ethyl 3,4- ethoxymethyl phenyl oil 319.26 319 12th ethyl 3-cyclopentoxy-4-methoxyphenyl oil 373.45 373 13th ethyl 3-methyl phenyl oil 273.33 273 14th ethyl 3-trifluoromethyl-phenyl oil 327.30 327

Reference Example 15

3-Hydroxy-1- (3-methylphenyl) -2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine

To a stirred suspension of 1.9 g (79 mmol) of magnesium turnings in 30 ml of anhydrous ether is added dropwise 5.9 ml of 79 mmol of bromoethane. Slight reflux begins after 1 ml is added. After all magnesium was added and consumed, the reaction mixture was cooled to 0 ° C and 8.7 g (50 mmol) of N- (3-methylphenyl) -2-pyrrolidone was added all at once. After warming to room temperature, stirring for 2 hours, the mixture was poured onto ice and extracted with ethyl acetate. The combined organic materials were washed with water and brine, dried over sodium. · »··

The filtrate was concentrated under reduced pressure to give 8.8 g of a white solid.

The above solid was dispersed in a mixture of 40 mL of benzene and 86 mL of 1N sodium hydroxide and 7.2 mL of 64 mmol oxalyl chloride was added with vigorous mechanical stirring. After stirring under reflux for 1.5 hours, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic materials were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. Yellow oil is obtained.

GCMS [M ⁺ ] 305.

The above intermediate is dissolved in 20 ml of anhydrous ethanol and treated with a solution of sodium methoxide in methanol (prepared by carefully adding 1 g of sodium to 10 ml of anhydrous methanol). After stirring under reflux for 1.5 hours, the mixture was concentrated under reduced pressure and water (100 mL) was added. The mixture was acidified to pH 3 with 6N hydrochloric acid, and the monohydrous yellow precipitate was filtered off and washed with water. Recrystallization from 75 ml of isopropyl ether gave 6.8 g of a pale yellow crystal.

115-116 ° C;

¹ H NMR (300 MHz, CDCl ₃ ) 1.16 (t, J = 7.2 Hz, 3H);

2.37 (s, 3H); 2.74-2.82 (m, 4H); 3.85 (t, J = 6.8 Hz, 2H); 7.08-7.14 (m, 3H); 7.30 (t, J = 7.7 Hz, 1H);

MS m / z [M ⁺ ] 259.

16-29. reference example

Reaction of the appropriate 2-pyrrolidinone with alkyl magnesium bromide followed by treatment with ethyl oxalyl chloride and alkaline

- 39 · · · · · »» »* * * * * *« «« «

By analogy to Reference Example 15, the following compounds of formula VI are obtained:

Reference example number R ¹ R ² mp (° C) molecular Weight Mass Spectrum [M ⁺ ] 16th methyl phenyl oil 231.25 231 17th ethyl phenyl 140-142 245.28 245 18th ethyl 4-fluoro- phenyl 133-135 263.27 263 19th methyl 4-methoxy- phenyl oil 261.28 262 20th ethyl 4-methoxy- phenyl 121-122 275.30 276 21st n- propyl 4-methoxy- phenyl 125-126 289.33 289 22nd ethyl 3-methoxy phenyl 129-130 275.30 275 23rd ethyl 2-methoxy phenyl 119-120 275.30 275 24th ethyl 4-methyl- phenyl 110-112 259.30 260 25th ethyl 2-methyl- phenyl oil 259.30 259 26th ethyl 3-trifluoromethyl-phenyl 117-118 313.28 313 27th ethyl 2-trifluoromethyl-phenyl oil 313.28 313

β · ·

Reference example number R ¹ R ² Mp (° C) molecular Weight Crowd- spectrum _ 28th ethyl 3,4- ethoxymethyl phenyl 179-180 305.33 306 29th ethyl 3-cyclopentoxy-4-methoxyphenyl 133-134 359.42 360

Reference Example 30

N- (2-M ethoxyphenyl) -2-pyrrole at g, 176 mmol of 2-pyrrolidone, 7.6 mL, 59 mmol of 2-iodoanisole,

A mixture of 7.5 g, 117 mmol copper powder, 8.1 g, 59 mmol potassium carbonate was stirred under a stream of nitrogen at 150 ° C. After 18 hours, the reaction mixture was filtered through a 6 x 15 cm pad, eluting with 1: 1 ethyl acetate: hexane to give a pale yellow oil. Unreacted reagents were removed by vacuum distillation at 0.6 mm Hg at 80-100 ° C to give 9.2 g of the title compound as a honey-like oil.

¹ H NMR (300 MHz, CDCl ₃ ) 2.20 (pentet, 2H), 2.55 (t, 2H); 3.75 (t, 2H); 3.82 (s, 3H); 6.93-7.02 (m, 2H); 7.25-7.30 (m, 2H);

MS m / z [M ⁺ ] 191.

31-39. reference example

Reaction of the appropriate iodine or bromobenzene with 2-pyrrolidinone gives, by analogy to Example 30, the following compounds of formula (V):

Reference example number R molecular Weight Mass Spectrum [M ⁺ ] 31st 4-methoxy- phenyl 191.22 191 32nd 3-methoxy phenyl 191.22 191 33rd 3-methylphenyl 175.23 175 34th 4-methylphenyl 175.23 175 35th 2-methylphenyl 175.23 175 36th 3-Trifluoro methylphenyl 229.20 229 37th 2-trifluoromethyl-phenyl 229.20 229 38th 3,4- ethoxymethyl phenyl 221.26 221 39th 3-cyclopentoxy-4-methoxyphenyl 275.35 275

• ·

Claims (7)

Claims A compound of formula (I) and pharmaceutically acceptable salts thereof, wherein R ¹ is hydrogen, (C 1 -C 7) alkyl, (C 2 -C 3) alkenyl, (C 3 -C 5) cycloalkyl, or methylene (C 3 -C 5) cycloalkyl), wherein each alkyl or alkenyl group is optionally substituted with up to two to two carbon atoms. they may be substituted by alkyl or trifluoromethyl or up to three halogen atoms, X is oxygen or two hydrogen atoms, R ² and R ³ independently of one another are hydrogen, C 1 -C 14 alkyl, C 1 -C 14 alkoxy, C 2 -C 7 alkenyl, C 4 -C 7 heterocyclic groups containing oxygen or sulfur, SO ₂ or NR ⁵ wherein R ⁵ is hydrogen, (C 1 -C 4) alkyl, or (II) wherein a is an integer from 1 to 5; b and c are 0 or 1, R ⁴ is hydrogen, hydroxy, C 1-5 alkyl, C 2 -C 6 alkenyl, C 1 -C 5 alkoxy, C 3 -C 6 cycloalkoxy, halogen, trifluoromethyl, CO ₂ R ⁶ , CONR ⁶ R ⁷ , NR ⁶ R ⁷ , NO ₂ or SO ₂ NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are each independently hydrogen or C 1-4 alkyl; where Z is oxygen or sulfur, SO ₂ or NR ⁸ where R ⁸ is hydrogen or C 1-4 alkyl, - Y is C 1-5 -alkylene or C 2-6 -alkenyl substituted with up to two C 1-7 -alkyl or C 3-7 -cycloalkyl optionally substituted with or a group of formula (a) wherein p is 1-3; . W is oxo or hydroxy; R ⁹ is C 1 -C 3 alkyl, wherein the alkyl, alkenyl, cycloalkyl, alkoxyalkyl, or heterocyclic groups may each be optionally substituted with 1 to 14, preferably 1 to 5, groups and such groups may be 1 to 3 carbon atoms; C 2 alkyl, trifluoromethyl or halogen, provided that when R ¹ is ethyl and R ⁴ is methylphenyl, R ^{3 must} not be hydrogen, methyl, phenyl, 4-fluorophenyl; or 2-pyridyl, and provided that when R ² is 4-methylphenyl and R ³ is 4-fluorophenyl, then R ¹ cannot be phenyl, methyl or n-propyl. and with the proviso that when R ¹ is ethyl, R ^{2 is} phenyl, then R ³ cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, and provided that R ^{1 is} ethyl and R ² is 4-methoxyphenyl, then R ³ cannot be 4-fluorophenyl. A compound according to claim 1, wherein R ¹ is C 1 -C 3 alkyl, R ² and R ³ are each independently C 3 -C 7 cycloalkyl, C 4 -C 7 SO _2, or a heterocyclic group of formula III, wherein a is an integer from 1 to 5, R ⁴ is hydrogen, hydroxy, C 1-5 alkyl, C 1-5 alkoxy, or halogen. • · The compound of claim 1, wherein R ¹ is ethyl or isopropyl, R ² is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl and R ³ is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfanyl, 4-fluorophenyl or 3,4-dichlorophenyl. Compounds according to claim 1: 3-ethyl-1- (4-methoxyphenyl) -6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-ethyl 1-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-Ethyl 1- (3,4-dichlorophenyl) -6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4- c] pyridine; 3-ethyl 1-1-cyclopentyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine; 3-Ethyl-1- (4-fluorophenyl) -6- (2-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4- c] pyridine; 3-ethyl 1-1-cyclopentyl-6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine; 3-ethyl 1-1-cyclopentyl-6- (3-trifluoromethyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclohexyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-isopropyl-1-cyclopentyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; • · 45 3-ethyl-1-cyclopentyl-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclopentyl-6- (2-methyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine; 3-ethyl 1- (3-sulfolanyl) -6- (3-methylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-ethyl-1- (3-sulfolanyl) -6- (3-methoxyphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-ethyl-1-cyclobutyl-6- (3-methyl-phenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine; 3-Ethyl-1- (3-sulfolanyl) -6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo [3,4-c] pyridine ; 3-Ethyl-1-cyclopropyl-6- (3-trifluoromethylphenyl) -7-oxo-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c] pyridine; 3-ethyl-1-1-cyclobutyl-6- (2-methylphenyl) -7-oxo-4,5 _I 6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine. A pharmaceutical composition for inhibiting the production of phosphodiesterase type IV (PDE) and tumor necrosis factor (TNF), comprising administering a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier. 6. A pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways diseases, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases related to the production of TNF, characterized in that the compound of claim 1 is pharmaceutically effective. with a pharmaceutically acceptable carrier. 8. A method of treating asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock, and other diseases associated with the production of TNF, wherein the therapeutically effective amount of with a pharmaceutically acceptable carrier.